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Immune-altering roles of progesterone and subsequent development of preeclampsia in artificial cycles of frozen embryo transfer

      To the Editors:
      Conrad et al
      • Conrad K.P.
      • von Versen-Höynck F.
      • Baker V.L.
      Potential role of the corpus luteum in maternal cardiovascular adaptation to pregnancy and preeclampsia risk.
      discussed in detail the possible risk factors for the development of hypertensive disorders of pregnancy (HDP) among women conceived by frozen embryo transfer cycles, specifically preeclampsia development in artificial cycles (frozen-thawed embryo transfer artificial cycle [FET-AC]). They discussed the role of relaxin and also suggested the possible role of suboptimal hormonal levels in the development of preeclampsia and HDP in women conceived by FET-AC. The process of decidualization and normal placentation is strictly controlled by certain levels of various inflammatory markers, the disruption of which may lead to abnormal placentation.
      • Al-Lami R.A.
      • Sibai B.M.
      • Salih S.M.
      Risk of preeclampsia in artificial cycles of frozen embryo transfer in vitro fertilization pregnancies.
      Less-than-physiological levels of estrogen and progesterone in FET-AC may contribute to improper decidualization and subsequent abnormal placentation, which could lead to placental ischemia and preeclampsia development later in pregnancy. Previously, we have explained the possible immune-altering roles of less-than-physiological levels of estrogen in the development of preeclampsia and placenta accreta spectrum in women conceived by FET-AC.
      • Al-Lami R.A.
      • Sibai B.M.
      • Salih S.M.
      Risk of preeclampsia in artificial cycles of frozen embryo transfer in vitro fertilization pregnancies.
      ,
      • Al-Lami R.A.
      • Salih S.M.
      • Sibai B.M.
      In vitro fertilization as an independent risk factor for placenta accreta spectrum.
      Suboptimal levels of progesterone may also contribute to abnormal decidualization and potentially to preeclampsia development in FET-AC through immune response alteration. Normally in pregnant women, endogenous progesterone can modulate the function of the innate and cellular immune response systemically and locally in the maternal–fetal interface and exhibit a net anti-inflammatory effect for successful pregnancy.
      • Shah N.M.
      • Lai P.F.
      • Imami N.
      • Johnson M.R.
      Progesterone-related immune modulation of pregnancy and labor.
      It was found that progesterone can inhibit the activation of various inflammatory cells (including uterine macrophages), suppress the nuclear factor kappa B signaling pathway, increase anti-inflammatory cytokines (eg, interleukin-10), and decrease proinflammatory ones (eg, tumor necrosis factor-α).
      • Shah N.M.
      • Lai P.F.
      • Imami N.
      • Johnson M.R.
      Progesterone-related immune modulation of pregnancy and labor.
      Further, progesterone favors a T helper type (Th)-2 response over a Th-1 response, with a subsequent heightened humoral response rather than a T-lymphocyte cellular immune response, which subsequently mitigates the inflammatory reaction.
      • Shah N.M.
      • Lai P.F.
      • Imami N.
      • Johnson M.R.
      Progesterone-related immune modulation of pregnancy and labor.
      It is thus reasonable that suboptimal levels of progesterone (as found in FET-AC) may lead to improper decidualization, placental ischemia, and preeclampsia development in addition to tolerance failure to paternal antigens and augmented inflammatory response, which collectively results in a higher risk of HDP and preeclampsia. It is therefore interesting to know and would be appreciated if Conrad and colleagues
      • Conrad K.P.
      • von Versen-Höynck F.
      • Baker V.L.
      Potential role of the corpus luteum in maternal cardiovascular adaptation to pregnancy and preeclampsia risk.
      can discuss other potential pathways through which suboptimal hormonal levels contribute to the development of HDP and preeclampsia in women conceived by FET-AC in addition to the hormones’ immune-altering roles that affect decidualization and subsequent placentation and their synergistic effects with relaxin.

      References

        • Conrad K.P.
        • von Versen-Höynck F.
        • Baker V.L.
        Potential role of the corpus luteum in maternal cardiovascular adaptation to pregnancy and preeclampsia risk.
        Am J Obstet Gynecol. 2022; 226: 683-699
        • Al-Lami R.A.
        • Sibai B.M.
        • Salih S.M.
        Risk of preeclampsia in artificial cycles of frozen embryo transfer in vitro fertilization pregnancies.
        Am J Obstet Gynecol. 2021; 225: 466-467
        • Al-Lami R.A.
        • Salih S.M.
        • Sibai B.M.
        In vitro fertilization as an independent risk factor for placenta accreta spectrum.
        Am J Obstet Gynecol. 2021; 225: 699
        • Shah N.M.
        • Lai P.F.
        • Imami N.
        • Johnson M.R.
        Progesterone-related immune modulation of pregnancy and labor.
        Front Endocrinol. 2019; 10: 198

      Linked Article

      • Risk of preeclampsia in artificial frozen embryo transfer as a result of insufficient corpus luteum hormone levels: a response
        American Journal of Obstetrics & Gynecology
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          We thank Dr Al-Lami for her interest in and comments on our recent Clinical Opinion titled “Potential role of the corpus luteum in maternal cardiovascular adaptation to pregnancy and preeclampsia risk”1. The concept that preeclampsia risk is increased in frozen embryo transfer cycles—specifically artificial cycles (FET-AC)—is largely based on observational studies, though randomized clinical trials (RCTs) are currently in progress. Even if RCTs corroborate this link, however, the underlying mechanisms will be difficult to prove without further interventional studies.
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